ArticleOncogene2021
Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 58 citations in OpenAlex.
- Therapeutic Resistance in Melanoma: Molecular Mechanisms and Emerging Pharmaceutical Strategies.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Review
- Inhibiting Fatty Acid Oxidation Reverses Autophagy-Mediated Acquired Chemotherapy Resistance in Pancreatic Ductal Adenocarcinoma.Cancer research · 2026Article
- An Itch Receptor Drives Melanoma.bioRxiv : the preprint server for biology · 2026Article
- FGFR1 but not S6K1/2 drives intrinsic BRAF inhibitor resistance in melanoma.Cell death discovery · 2026Article
- Co-targeting CDK4/6 and MEK reverses mesenchymal transition in therapy-refractory BRAF-altered pediatric high-grade glioma.Journal of experimental & clinical cancer research : CR · 2026Article
- mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway.Cell death & disease · 2026Article
- BRAF inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations.Molecular biomedicine · 2026Review
- Micrometastasis-derived models enable drug testing for early-stage, high-risk melanoma patients.EMBO molecular medicine · 2026Article
- MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis.Nature communications · 2025Article
- Decoding breast cancer: insights into molecular pathways & therapeutic approaches.Discover oncology · 2025Review
- Elevated NR2F1 underlies the persistence of invasive disease after treatment of BRAF-mutant melanoma.The Journal of clinical investigation · 2025Article
- MAPK and mTORC1 signaling converge to drive cyclin D1 protein production to enable cell cycle reentry in melanoma persister cells.Science signaling · 2025Article
- MADSP: predicting anti-cancer drug synergy through multi-source integration and attention-based representation learning.Bioinformatics (Oxford, England) · 2025Article
- Cancer Stem Cells and the Renin-Angiotensin System in the Tumor Microenvironment of Melanoma: Implications on Current Therapies.International journal of molecular sciences · 2025Review
- Global trends and emerging insights in BRAF and MEK inhibitor resistance in melanoma: a bibliometric analysis.Frontiers in molecular biosciences · 2025Article
- Single-cell profiling deciphering cholesterol metabolism dysregulation in metastatic uveal melanoma and implicating SLC45A2 in its prognosis.Frontiers in immunology · 2025Article
- Cancer 3D Models: Essential Tools for Understanding and Overcoming Drug Resistance.Oncology research · 2025Review
- Inhibition of PI3K/Akt/mTOR Signaling Pathway Suppresses 5-Fluorouracil Resistance in Gastric Cancer.Molecular biotechnology · 2024Article
- Combined inhibition of KRASNature communications · 2024Article
Corrections and comments
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Authors and funding
22 authors at 8 institutions in 2 countries.
Funding
Abstract
Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.